ITR: Collaborative Research: (ASE+NHS+EVS)-(sim+dmc+int): In Silico De Novo Protein Design: A Dynamically Data Driven, (DDDAS), Computational and Experimental Framework

摘要：Dimitrios Morikis机构：加州RiversideProposal编号：0427103研究：在计算蛋白质设计的一个挑战是发现新的蛋白质，这是兼容的目标模板结构或任意的三维结构。本研究是一个动态数据驱动的应用系统（DDDAS），通过一个综合的研究框架（即，计算、物理化学和生物化学方法）用于肽和蛋白质的计算机从头设计。该项目的主要目的是（i）通过基于混合整数优化和确定性全局优化的新型计算框架进行计算机序列选择和折叠特异性计算，（ii）通过NMR、结构测定和分子动力学进行体外和计算机表征，（iii）预测序列的蛋白质表达、结构表征和活性测量，以及（iv）开发一个基于网络的WorkBench支持系统，用于从头肽/蛋白质设计，该系统将免费提供给所有研究人员。用于测试和验证所提出的框架的生物系统包括C3 a过敏毒素（aims（i）-（iv））和人β防御素（aims（i），（ii）和（iv）的分子动力学）。智力优势：计划的工作涉及来自三个机构（普林斯顿大学、美国）的跨学科团队（Floudas、Lambris、Morikis）。宾夕法尼亚大学加州，位于滨江）。他们的专业知识涵盖补体生物学，蛋白质化学，结构生物学，数学建模和分析，组合和全局优化，科学计算和生物工程等领域，该项目是一个综合的计算和实验工作。这些发展可以大大加快药物发现过程，解决新药设计中的重要任务，提出的基于Web的WorkBench的新概念将是科学界的第一个此类服务。 更广泛的影响：利用IT和DDDAS技术，在一个独特的共生计算和实验框架中，该项目将为在新药发现方面取得重大进展奠定基础。这个框架用于在计算机上预测选择性折叠到结构模板的新序列及其实验验证，将允许快速筛选新的替代品，并将导致更好和更快的药物发现，这对我们的社会产生直接影响。拟议的努力将研究生、博士后和本科生的参与纳入研究，从而提供多学科培训机会。合作PI有记录的研究与本科生作为他们的初级独立工作的一部分，以及高级论文工作。这三所院校都有吸引传统上代表性不足的群体的学生和雇员的政策。合作PI致力于与这些学生合作，并将积极主动地吸引他们参加这个研究项目，研讨会系列，期刊俱乐部和研究生课程。合作PI在教育本科生和研究生以及来自代表性不足群体的博士后研究员方面有着良好的记录。研究结果将通过在档案期刊上发表，参考程序以及通过会议上的演讲传播给整个科学界。此外，基于网络的肽/蛋白质从头设计工作台的开发将首次为科学界提供服务。

ABSTRACTPI: Dimitrios Morikis Institution: University of California RiversideProposal Number: 0427103Research: A challenge in computational protein design is the discovery of novel proteins, which are compatible with either target template structures or arbitrarily three dimensional structures. This research is a dynamically data driven application systems, (DDDAS), effort through an integrative research framework, (i.e., computational, physicochemical, and biochemical approaches) for the in silico de novo design of peptides and proteins. The primary aims of the project are (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, (iii) protein expression, structural characterization and activity measurements of predicted sequences, and (iv) the development of a web-based WorkBench support system for de novo peptide/protein design which will be freely available to all researchers. The biological systems for testing and validating the proposed framework include the C3a anaphylatoxin (aims (i)-(iv)), and human beta defensins (aims (i), molecular dynamics of (ii) and (iv)). Intellectual Merit:The planned effort involves an interdisciplinary team (Floudas, Lambris, Morikis) from three institutions (Princeton, U. Penn, U. California at Riverside). Their expertise spans the fields of complement biology, protein chemistry, structural biology, mathematical modeling and analysis, combinatorial and global optimization, scientific computing, and bioengineering, and the project is an integrative computational and experimental effort. These developments can expedite significantly the drug discovery process, address important tasks in the design of new drugs, and the proposed novel concept of a web-based WorkBench will be the first such service to the scientific community. Broader Impacts: Using IT and DDDAS techniques, in a uniquely symbiotic computational and experimental framework, this project will lay the groundwork for making significant advances in the discovery of new drugs. This framework for in silico prediction of new sequences which fold selectively to structural templates and their experimental validation will allow rapid screening of novel alternatives and will lead into better and faster drug discovery which has direct impact in our society. The proposed effort integrates participation of graduate students, postdoctoral students, and undergraduate students into the research, thereby providing multidisciplinary training opportunities. The co-PIs have records in research with undergraduate students as part of their junior independent work, as well as senior thesis work. All three institutions have policies for attracting students and employees from traditionally under-represented groups. The co-PIs are committed to working with these students and will work pro-actively to attract them to this research project, the seminar series, the journal club, and the graduate level course. The co-PIs have strong records of educating undergraduate and graduate students, and post-doctoral associates from under-represented groups. The results of the research will be disseminated to the entire scientific community through publications in archival journals, refereed proceedings, and via presentations at conferences. Furthermore, the development of the web-based WorkBench for the de novo design of peptide/proteins will provide, for the first time, service to the scientific community.